Obesity and hypertension are serious public health concerns. Population studies indicate that at least two- thirds of the prevalence of hypertension can be directly attributed to obesity. Obesity-induced hypertension is associated with sympathetic overactivity and evidence indicates that signaling through both leptin receptor and melanocortin-4 receptor is critical for this process. However, the underlying neural basis of this association remains incompletely understood. Our long-term goal is to delineate the neural circuits that mediate obesity- induced sympathetic overactivity and hypertension. The rationale for this proposed research is that understanding the specific brain leptin and melanocortin circuits that mediate sympathetic outflow and blood pressure will help to develop more selective pharmacologic strategies that will allow effective treatment of hypertension and obesity. We have recently identified a unique subpopulation of neurons in the lateral hypothalamic area that co-express both leptin receptor and melanocortin-4 receptor. The central hypothesis is that, in the context of obesity and hyperleptinemia, both leptin receptor and melanocortin-4 receptor signaling in this subpopulation of lateral hypothalamic area neurons is augmented to cause sympathetic overactivity and hypertension. In order to directly test the components of this hypothesis, the following Specific Aims have been generated: 1) To determine if MC4R signaling in the LHA is necessary and sufficient to regulate renal SNA and mediates obesity-associated increases in blood pressure; and 2) To determine if LepR signaling in the LHA is necessary and sufficient to regulate renal SNA and mediates obesity-associated increases in blood pressure; and 3) To test if selective optogenetic modulation of activity of LHA LepR+ neurons regulates renal SNA and ameliorates obesity-associated increases in blood pressure. We will test if manipulating leptin and melanocortin signaling and neuronal activity in the LHA in the context of obesity affect sympathetic outflow and cardiovascular function. The proposed research is innovative because it will combine multiple state-of-the-art techniques, including Cre/loxP, optogenetics, direct multi-fiber recording of sympathetic nerve activity and radiotelemetry measurement of blood pressure, to test a novel brain circuit that contributes to obesity-induced sympathetic overdrive and hypertension in mice. The proposed research is significant because it will improve our understanding of the molecular and neural basis of obesity-induced hypertension and identifies novel therapeutic opportunities to effectively treat hypertension associated with the development of obesity. We believe that this work will contribute to a better understanding of how brain networks and signaling pathways lead to the development of neurogenic hypertension.